Gastric cancer ranks high among the leading causes of cancer-related deaths worldwide, with 989,000 new cases and 738,000 deaths each year. The majority of human stomach tumors are associated with chronic infection with the bacterial pathogen Helicobacter pylori. As approximately half of the world's population is infected, Helicobacter infection contributes significantly to the worldwide gastric cancer burden. It is critical to understand the factors that lead to the transition from inflammatory disease to gastric cancer. In patients infected with H. pylori, it is thought that the inflammation induced in respons to the bacteria is the major determinant in the development of gastric malignancy. However, the regulatory mechanisms of Helicobacter-induced inflammation are still not well understood. In addition, the mechanisms of Helicobacter-induced gastric carcinogenesis are still unclear. We recently showed using a mouse model of gastric cancer that a key signal transduction adaptor protein, myeloid differentiation primary response gene 88 (MyD88), regulates Helicobacter-induced gastric cancer progression. Our overall hypothesis is that the dramatic increase in progression to gastric cancer found in MyD88 deficient mice is due to overactivation of the alternative TRIF-mediated signaling pathway, leading to overproduction of a specific set of TRIF-regulated pro-neoplastic inflammatory factors in the gastric tissue. To test this hypothesis, we will use our recently published accelerated mouse model of gastric cancer to investigate the role of MyD88/TRIF signaling in Helicobacter-stimulated inflammatory microenvironment. The following specific aims will be addressed in the proposed study: Specific aim 1: Investigate the role of hyperactivated TRIF pathway in Helicobacter-induced gastric neoplasia; Specific aim 2: Determine genes involved in accelerated Helicobacter-induced gastric cancer progression. This work first seeks to discover a new gastric cancer progression risk factor during Helicobacter-induced chronic inflammation. Second, this work will identify key gastric cancer gene candidates that are important in the development and progression of gastric cancer.